As an antidepressant there has already been commercially available methyl threo-2-phenyl-2-(2'-piperidinyl)acetate hydrochloride (trade name: Ritalin) in the form of racemic modification. It is also known that methyl threo-2-phenyl-2-(2'-piperidinyl)acetate hydrochloride exhibits a pharmacologic activity about 5 times higher in the form of a specific stereoisomer than in the form of other stereoisomers (U.S. Pat. No. 2,957,880).
Further, the structural analysis of an optically active methyl 2-phenyl-2-(2'-piperidinyl)acetate, which exhibits a higher pharmacologic activity than Ritalin as an antidepressant, has been under way. A report has been made on the absolute configuration of these optically active materials (J. Med. Chem., 12, 266, 1969). A method for economic and simple preparation of such an optically active 2-phenyl-2-(2'-piperidinyl)acetate derivative from a 2-phenyl-2-(2'-piperidinylidene)acetate derivative has already been applied for patent (Japanese Patent Application No. 9-72570).
No reports have been made on method for the preparation of a 2-phenyl-2-(2'-piperidinylidene)acetate derivative from a 2-phenyl-2-(2'-piperidinylidene) acetonitrile derivative. Thus, it has been keenly desired to establish such a preparation method.
As a method for the synthesis of a 2-phenyl-2-(2'-piperidinylidene)acetonitrile derivative there is disclosed a method which comprises reacting piperidone (formula (8)) as a starting material with diphosphorus pentasulfide to synthesize a thiolactam form, reacting the thiolactam form with methyl iodide (hereinafter referred to as "MeI") in the presence of potassium hydroxide to synthesize a lactim thioether form (formula (9)), and then allowing the lactim thioether form to undergo condensation reaction with benzyl cyanide in the presence of 1, 5-diazabicyclo[4.3.0]-5-nonene (hereinafter referred to as "DBN") in the same amount as the lactim thioether form thus obtained to prepare 2-phenyl-2-(2'-piperidinylidene)acetonitrile (formula (4)), as carried out in the following reaction formula (Indian J. Chem., Sect. B, 17B(2), 104-106, 1979). ##STR3##
However, this synthesis method leaves something to be desired on an industrial basis. In other words, this synthesis method requires a complicated procedure and multiple reaction steps. This synthesis method is also disadvantageous in that the starting material is not easily available and DBN, which is expensive, must be used in the same amount as the intermediate. Thus, an economical preparation method feasible on an industrial basis has been desired.
Further, no reports have been made on the synthesis of a 2-phenyl-2-(2'-piperidinylidene)acetonitrile derivative involving the use of a metal complex.